Keywords
Cancer immunotherapy - PD-1/PD-L1 - T cell exhaustion - conventional chemotherapy
Introduction
Chimeric antigen receptor (CAR)-T cell therapy is a type of immunotherapy in which
T cells are genetically altered with specialized tumor-killing powers using CAR. In
recent years, CAR-T cells against CD19 have demonstrated exceptional therapeutic success
in treating B-cell hematologic malignancies.[1] The FDA approved two CAR-T medicines that target CD19, tisagenlecleucel (KYMRIAH)
and axicabtagene ciloleucel (YESCARTA), In recent years, CAR-T cells for a wide range
of solid cancers have been produced and tested. To date, approximately 200 clinical
trials of CAR-T cells targeting solid tumors have been launched worldwide, with the
majority of studies on antigens involving mesothelin (MSLN), ganglioside (GD2), glypican-3
(GPC3), human epidermis growth factor receptor 2 (HER2), carcinoembryonic antigen
(CEA), epidermal growth factor receptor and its variants (epidermal growth factor
receptor, EGFR/EGFRvIII), prostate-specific membrane antigen (PSMA), prostate stem
cell antigen (PSCA), and claudin 18.2.[2]
Cancer Immunotherapy is a new approach in which the immune system is used for the
detection and killing of cancer cells with great accuracy. This has been highly highlighted
lately since it has the potential to be used to positively modulate the immune response
toward cancer. The immune system has intrinsic protective responses that guard against
damage to host tissues and organs while circumventing the toxic effects of overly
aggressive immune responses.; these cancer cells use the principles of the immune
system's regulation to avoid immune detection and in some cases, even turn against
the immune systems.[3] The most notable regulatory components are programmed cell death 1 receptor (PD-1),
its ligand (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Blocking
all these pathways has emerged as one of the most effective methods of treating cancer.[4] Following the resolution of the role played by the PD-1/PD-L1 pathway in immune
evasion, antibodies against this pathway are currently used as the primary therapeutic
approach to various types of cancers. These include melanoma, lung cancer, lymphoma,
and liver cancer, among others. They are employed in colorectal cancer, urothelial
cancer, head and neck squamous cell carcinoma, cervical cancer, kidney cancer, stomach
cancer, and breast cancer. These antibodies block this pathway so as to improve the
immune recognition and attack by the immune system on tumor cells and thus present
a more targeted and effective treatment in patients across a broad spectrum of different
cancer types.[5] Immune checkpoints are a group of immuno-regulatory processes that help to minimize
collateral tissue damage, avoid autoimmunity, and preserve self-tolerance.[6] Immune checkpoint pathways provide cancer cells with an escape route from the anti-tumor
immune onslaught.[7] The beginning and modulation of the immune response depend on T-cell activation.
Antigen-presenting cells (APCs) must co-stimulate with a "two-signal" in order for
naive T-cells to be effectively activated in response to an antigen and for the immune
response to follow.[8] One well-known immune checkpoint inhibitor mechanism is the programmed death-1 (PD-1)/programmed
death-1 ligand-1 (PD-L1) axis. A significant fraction of tumor-infiltrating lymphocytes
across a wide range of tumor types expresses the T-cell coinhibitory receptor PD-1.[9] The clinical activity of PD-1/PD-L1 blockade is observed in less than 40% of patients
and hence, there's a need for further elucidation of these immune checkpoint molecules.
This review has dealt with molecular mechanisms of PD-1/PD-L1 immune checks and their
role in TME and the normal immune system. Understanding the processes involved the
researchers hope to correct the deficiencies in PD-1/PD-L1 inhibitors. The combination
therapies have emerged as promising approaches to enhance treatment efficacy. These
include combinations of PD-1/PD-L1 inhibitors with more conventional approaches to
treatment, such as radiation, chemotherapy, targeted therapies, and anti-angiogenic
treatments. Other modalities of immunotherapy, including adoptive cell transfer and
cytokine-based treatments, are also now being investigated in combination with dietary
therapy aimed at enhancing the immune response in patients whose survival may be enhanced.
This shall help overcome resistance and maximize the therapeutic potential of PD-1/PD-L1
blockades in cancer management.[10] One of the primary determinants of carcinogenesis was thought to be the interaction
between cancer cells and the immune system.[11]
T-Cell Exhaustion
In the context of malignancy or persistent infection, T-cell exhaustion is more common.
T-cell function gradually declines because of the condition, particularly in terms
of cytokine generation, proliferation, and target cell death. Interestingly, T-cell
fatigue in cancer is one of the primary barriers to the effectiveness of immune responses
directed against tumor cells.[12]
Mechanism of T-Cell Exhaustion
Mechanism of T-Cell Exhaustion
Chronic Antigen Exposure:
T-cell activation persists after repeated exposure to tumor antigens. In due course,
this corresponds with the T cells' increasing weariness. Normal turnover and differentiation
are typically exceeded by chronic stimulation, driving T cells into a dysfunctional
state.[13]
Upregulation of Inhibitory Receptors:
Overexpression of some inhibitory receptors on T cells leads to dysfunction known
as T-cell exhaustion. It weakens the immune system in its ability to effectively counteract,
for example, conditions such as cancer and several infections. Some key inhibitory
receptors are TIM-3 (T Cell Immunoglobulin and Mucin Domain-Containing Protein 3),
LAG-3 (Lymphocyte Activation Gene-3), and PD-1 (Programmed Death-1), among others.
These receptors are known to modulate the activation and function of T cells dampening
them and are prone to being disrupted by chronic antigen exposure, immune suppression
due to a tumor microenvironment, and by certain environmental pollutants. Overactivation
of these pathways in inhibitory settings fosters an avenue for tumors to evade immune
surveillance and produce even more tumor-enhancing immuno-suppressive microenvironments.
Thus, gaining insights into these mechanisms will be required to formulate therapies
reversing exhaustion of T-cell activation like checkpoint inhibitors and combination
immunotherapies to reconstitute strong immune responses.[14]
Transcriptional and Epigenetic Changes:
T-cell exhaustion is determined by transcriptional reprogramming, which largely contributes
to the levels of gene expression in exhausted cells. Such rapid reprogramming appears
central to the establishment and maintenance of the exhausted phenotype. Among such
important transcription factors are NR4A and TOX (Thymocyte Selection-Associated High
Mobility Group Box), which contribute importantly to the sustained exhausted phenotype,
meaning they also represent a subject of scientific investigation and, hence, could
represent a potential therapeutic intervention. In addition to those mentioned above,
other epigenetic modifications that contribute to T-cell exhaustion stability and
persistence include DNA methylation processes and histone modifications, which can
lead to heritable changes that consolidate the exhaustion state over time. Epigenetic
changes serve to embed T-cells in a state of reduced functionality and impair their
capacity to evoke appropriate immune responses. T-cell exhaustion: transcriptional
and epigenetic interplay Understanding this interplay would open avenues for developing
therapies that rejuvenate T-cell activity, thereby improving the performance of the
immune system in fighting cancer and chronic infection.[15]
Metabolic Dysfunction:
The fatigued T cells' metabolic condition is characterized by malfunctioning glycolysis
and mitochondria. The impaired energy production that results from this metabolic
dysregulation ultimately prevents the cells from producing enough energy to sustain
their ability to respond effectively. This metabolic stress is exacerbated, and T-cell
fatigue is increased by tumor microenvironments, which are frequently hypoxic and
nutrient deficient.[16]
Immunosuppressive Tumor Microenvironment:
Tumor-associated macrophages, myeloid-derived suppressor cells, and Tregs are among
the immune-suppressive cells that are typically more prevalent in the tumor microenvironment.
TGF-β and IL-10, two immunosuppressive cytokines secreted by these cells, have the
power to reduce T cell activity and cause fatigue.
ZeroIt also secretes substances that prevent T cell activation and function, such
as adenosine and indoleamine 2,3-dioxygenase (IDO).[17]
Loss of Co-stimulatory Signals:
Besides the signals derived from antigen recognition through the T cell receptor (TCR)
and the co-signaling molecules, co-stimulatory signals can activate T cells. In cancer,
an exhausted T-cell is unable to send appropriate co-stimulation because it loses
the expression of co-stimulatory molecules like CD28, carrying out their function.[18]
Altered Cytokine Signaling:
Chronic exposure to some key cytokines in the tumor microenvironment serves to induce
the exhaustion state in T cells. Equally important, the lack of some main pro-inflammatory
cytokines, especially those needed for T cell activation and proliferation, such as
IL-2 and IL-12, is involved in the generation of the exhausted phenotype.[19]
Mechanisms of T cell Exhaustion in cancer are shown in the below [Figure 1].
Fig. 1 depicts a visual representation of how different factors contribute to T cell exhaustion
in the context of cancer.
Tumor Microenvironment and PD-L1 Expression
Tumor Microenvironment and PD-L1 Expression
Induced Expression: Tumor cells upregulate PD-L1 in response to inflammatory signals,
specifically IFN-γ from immune cells. This initiates the process of adaptive immune
resistance, in which tumor cells exploit the PD-1/PD-L1 pathway to make themselves
immune attack-resistant. Constitutive Expression: Certain malignancies have a high
constitutive expression of PD-L1, which is unrelated to the immune system. Genetic
changes, including but not limited to amplification of the PD-L1 gene, can activate
numerous carcinogenic pathways, including PI3K/Akt, leading to this type of expression.[20]
Role in Sustaining Exhaustion
Role in Sustaining Exhaustion
Sustained Inhibition: The tumor microenvironment's PD-L1 persistence in PD-1 engagement
helps to keep T cells in a state of exhaustion. T cells that reach this state of exhaustion
exhibit a progressive loss of function, which includes the loss of their cytotoxic
potential, proliferative ability, and cytokine production. Alterations in transcription
and epigenetics: Prolonged PD-1 signaling can also stimulate these modifications,
locking the T cell in the fatigued state. The tired phenotype, for example, is supported
by the activation of the transcription factors TOX and Eomesodermin (EOMES). DNA methylation
at important loci is one epigenetic modification that stabilizes this dysfunctional
state.[21]
Combination Immunotherapy with CAR T Cells and Checkpoint Blockade
Combination Immunotherapy with CAR T Cells and Checkpoint Blockade
CPB therapy has shown a lot of promise in activating exhausted immune cells, and there
is considerable potential for long-term clinical responses. However, the absolute
response rates are, at best, suboptimal and usually due to a lack of infiltrating
T cells that have some reactivity against the tumor within the tumor microenvironment.
To overcome these deficiencies, CAR T cells are of high promise, as they are bespoke
engineered immune cells designed to target and destroy tumor cells in a manner that
is unmatched in terms of specificity for an antitumor response. CPB agents may add
the possibility of improving therapeutic benefits even further by combining them with
CAR T cells. It can neutralize the immunosuppressive factors that exist in the tumor
microenvironment. Likely, such will inhibit the effectiveness of CAR T cells. The
result could be a stronger and more resilient immune response to cancer. Ongoing,
both in preclinical and clinical studies; synergy is being explored in CAR T-cell
therapy with CPB agents, more specifically in the treatment of solid tumors, an area
that has been a very difficult challenge to achieve with immunotherapies; integration
of these therapies combines them into better outcomes for patients affected by malignancies
of solid tumors to potentially evade resistance.[22]
CPB Checkpoints
These checkpoints regulate the immune system, balancing activation and inhibition
of T cells to prevent autoimmune conditions. Major examples include TIM3, CTLA-4 (CD154),
PD-1 (CD279), and its ligand PD-L1 (CD274; B7-H1), as well as the antigen with LAG3
receptor activity (LAG3; CD223). Disruption of these regulatory mechanisms can cause
severe malfunction in the immune system. For instance, through the downregulation
or deletion of CTLA-4, there is overstimulated lymphocyte proliferation and massive
autoimmune responses resulting in fatal outcomes. Therefore, a straightforward understanding
of these checkpoints, including their functions and mechanism of action, will provide
necessary insight into both immune homeostasis as well as the therapeutic manipulation
of immune responses in diseases like cancer and autoimmunity.[23] Inhibition of CTLA-4 signaling has been demonstrated to cause tumor regression in
cancer model organisms and thus seems to represent an effective therapeutic approach.
In contrast, overexpression of PD-L1 in the tumor supports tumor progression as well
as immune escape, and interference with PD-L1 signaling causes tumor regression in
most models of cancer. However, this redundancy in signaling has a side effect that
is causing T cell exhaustion and loss of immune responses in models of infection,
leading to chronic infections. These observations underscore the critical complexity
of immune checkpoints in oncology but also in infection and underline the development
of targeted therapies that could modulate these pathways for therapeutic benefit.[24] Immune checkpoints are expressed by cancer cells to restrict anticancer responses.
Since both tumor cells and host cells, such as fibroblasts, dendritic cells, macrophages,
and B and T cells, can express PD-L1, the tumor microenvironment is full of inhibitory
PD-L1 signals. PD-L1 expression may occur in response to immune cell activation or
independently of it, reflecting an adaptive cancer response to immune infiltration.[25] When the PD-L1 gene's regulation 30 regions are disrupted or oncogenic pathways
including phosphatidylinositol 3-kinase/Akt, EGFR, STAT3, MYC, and cyclin-dependent
kinase 5 are activated, cancer cells may also spontaneously express PD-L1.[26]
Conventional Chemotherapy Combined with α–PD–1/PD–L1
Conventional Chemotherapy Combined with α–PD–1/PD–L1
Chemotherapy Modifying the Tumor Microenvironment (TME)
Chemotherapy mostly slows down the growth of tumors by stopping the cell cycle, preventing
DNA replication, altering cellular metabolism, or reducing microtubule assembly.[27] Furthermore, oxaliplatin and anthracycline, two cytotoxic chemotherapy medications,
have the ability to trigger the antitumor immune response and cause immunogenic cell
death.[28] Damage-associated molecular patterns induce cell death in immune cells, well known
for their role in the induction of immune responses, which include secretion of type
I interferons or IFN-I; exposure of endoplasmic reticulum proteins such as calreticulin
on the surface of the cell, acting as an "eat-me" signal; leakage of ATP; and release
of the nuclear protein high-mobility group box 1 (HMGB1). These molecular signals are important for the activation of the immune system
in terms of the recognition and elimination of dying tumor cells, thus contributing
to an immune response against cancer.[29] On dendritic cells (DCs), the receptors for CRT, ATP, and HMGB1 are TLR4, P2RX7,
and CD91. DCs are drawn to the tumor bed by the ATP-P2RX7 signaling; they are encouraged
to ingest cancer antigens by the CRT-CD91 axis; and the best possible presentation
of cancer antigens is facilitated by the HMGB1-TLR4 pathway.[30] By working together, DC's ability to acquire and deliver antigens is improved, which
in turn stimulates the adaptive immune response against cancer. Chemotherapy, when
administered at a level lower than the maximum tolerated dose, has the potential to
directly destroy immune suppressor cells in addition to causing immunogenic cell death.[31] Circulating and tumor-infiltrating regulatory T cells (Tregs) were diminished by
low-dose cyclophosphamide.[32] Furthermore, paclitaxel-induced a repolarization of tumor-associated macrophages
(TAM) from an M2-like to an M1-like phenotype. It is worth noting that certain chemotherapeutic
treatments have been shown to raise the circulating levels of myeloid-derived suppressor
cells (MDSCs) in cancer patients, despite the fact that these agents have been shown
to decrease the number of MDSCs in mice models.[33] The MDSC reduction induced by chemotherapy hence requires more validation in cancer
patients. Along with suppressor cells, various chemotherapy drugs, including vinblastine,
cyclophosphamide, and gemcitabine, also attracted and activated DC through the process
of immunogenic cell death.[34] IL-12 secretion may be directly boosted by chemotherapy medications including vinblastine,
5-fluorouracil, and oxaliplatin.[35] Furthermore, pemetrexed improved mitochondrial biogenesis, which increased TIL activation
independently of immunogenic cell death.[36]
<Insert [Table 1] here>
Table 1
Chemotherapy and the Tumor Microenvironment (TME)[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
|
Chemotherapy Drug
|
Mechanism of Action
|
Impact on TME
|
|
Cytotoxic Drugs
|
Arrest cell cycle, inhibit DNA replication, disturb cell metabolism, suppress microtubule
assembly
|
Direct tumor cell killing
|
|
Immunogenic Cell Death Inducers (e.g., anthracycline, oxaliplatin)
|
Release of damage-associated molecular patterns (DAMPs)
|
Stimulate antitumor immune response by activating dendritic cells (DCs)
|
|
Immune Suppressor Cell Depletion (e.g., cyclophosphamide)
|
Reduce regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs)
|
Enhance effector cell function
|
|
Immune Effector Cell Activation (e.g., vinblastine, 5-fluorouracil, oxaliplatin)
|
Promote DC activation and IL-12 secretion, enhance TIL activation
|
Strengthen antitumor immune response
|
Chemotherapy-based Immunotherapy
Chemotherapy-based Immunotherapy
Chemotherapy in conjunction with α-PD-1/PD-L1 inhibitors is yet another promising
approach for immediate and long-term control of the disease. This modality of treatment
is already confirmed to be a new standard of care for certain subsets of patients
with cancer and is currently being tested in many clinical trials for the safety and
effectiveness of this approach. For nonsquamous NSCLC, pembrolizumab in combination
with carboplatin and pemetrexed has been very effective. KEYNOTE-021 was a phase 2
clinical trial where patients treated with this combination demonstrated improved
PFS and higher response rates compared with patients who received chemotherapy alone.
The FDA approved pembrolizumab plus chemotherapy in the first line for patients with
advanced non-squamous NSCLC, regardless of the level of PD-L1 expression, following
the report of KEYNOTE-021 results. This established the potential that the combination
of immune checkpoint inhibitors with conventional chemotherapy could augment the treatment
efficacy of patients with advanced lung cancer.[37] Subsequently, pembrolizumab plus conventional chemotherapy improved NSCLC patients'
overall survival (OS) and progression-free survival (PFS) compared to chemotherapy
alone in two phase 3 clinical trials (KEYNOTE-189 and KEYNOTE-407).[38]
[39] Due to KEYNOTE-407 results, the FDA approved pembrolizumab in combination with chemotherapy
for squamous non-small cell lung cancer in 2018. Based on a series of successful trials
(KEYNOTE-355, KEYNOTE-590, and KEYNOTE-811), pembrolizumab plus chemotherapy was added
to the list of indications for advanced triple-negative breast cancer (TNBC), esophageal
cancer, and gastroesophageal junction cancer (GEJC).[40]
[41]
[42] Based on the results from the ORIENT-11 trial, the National Medical Products Administration
(NMPA) in China approved the combination of sintilimab, pemetrexed, and platinum as
a first-line treatment for advanced non-squamous non-small cell lung cancer (NSCLC).[43] Similarly, in 2020, the NMPA also approved the combination of camrelizumab, pemetrexed,
and carboplatin as a first-line treatment for non-squamous NSCLC, based on the findings
from the CameL trial.[44] In 2021, the NMPA continued to grow its approvals, tislelizumab as a combined use
with chemotherapy in the treatment of NSCLC and camrelizumab as a combined use with
gemcitabine and cisplatin in advanced nasopharyngeal carcinoma therapy. All these
approvals represent the growing consensus that the immunotherapy drugs, and their
combinations, are parts of the first-line therapy for many cancers, including NSCLC
and NPC.[45]
[46] Advanced NSCLC that is not squamous: carboplatin is given as first-line. Agents
like atezolizumab, an inhibitor of the α-PD-L1 protein, have received FDA approval
in combination with chemotherapy for several cancers. Atezolizumab plus nab-paclitaxel
in TNBC has been approved after the results of the IMpassion130 trial, and atezolizumab
with carboplatin plus etoposide has received approval in SCLC following results from
the IMpower133 trial. In addition to that, atezolizumab, nab-paclitaxel, and carboplatin
triplet were approved for advanced non-squamous NSCLC in the results of the IMpower130
trial. For SCLC, post-CASPIAN trial results have made durvalumab, in combination with
platinum and etoposide, approved in the US. Several chemoimmunotherapeutic combinations,
incorporating α-PD-1/PD-L1 inhibitors, are also under review in the United States
and China, with many awaiting clearances. The trend is on an upward trajectory in
combining immune checkpoint inhibitors with chemotherapy across a broad spectrum of
cancers.[47]
[48]
[49]
<Insert [Table 2] here>
Table 2
Chemotherapy Combined with α-PD-1/PD-L1[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
|
Cancer Type
|
Chemotherapy Regimen
|
α-PD-1/PD-L1 Agent
|
Clinical Trial
|
Approval Status
|
|
Non-squamous NSCLC
|
Carboplatin + Pemetrexed
|
Pembrolizumab
|
KEYNOTE-021, KEYNOTE-189, KEYNOTE-407
|
FDA, NMPA (China)
|
|
Squamous NSCLC
|
Carboplatin + Pemetrexed
|
Pembrolizumab
|
KEYNOTE-407
|
FDA
|
|
Triple-negative breast cancer (TNBC)
|
Nab-paclitaxel
|
Atezolizumab
|
IMpassion130
|
FDA
|
|
Esophageal cancer
|
−
|
Pembrolizumab
|
KEYNOTE-590
|
FDA
|
|
Gastroesophageal junction cancer (GEJC)
|
−
|
Pembrolizumab
|
KEYNOTE-811
|
FDA
|
|
Nasopharyngeal carcinoma
|
Gemcitabine + Cisplatin
|
Camrelizumab
|
CameL
|
NMPA (China)
|
|
Small cell lung cancer (SCLC)
|
Carboplatin + Etoposide
|
Atezolizumab, Durvalumab
|
IMpower133, CASPIAN
|
FDA
|
This table is not exhaustive, and there are many other ongoing clinical trials evaluating
chemotherapy combined with α-PD-1/PD-L1 for various cancer types. The approval status
may vary depending on the specific region.
The Role of PD-1/PD-L1 in Cancer Immunotherapy and Immune Evasion
The Role of PD-1/PD-L1 in Cancer Immunotherapy and Immune Evasion
A cell surface receptor called PD-1 was first shown to be preferentially expressed
in apoptotic cells.[50] PD-1 was later discovered to be the primary immunological checkpoint controlling
T and B cell antigen response thresholds. PD-1 is a critical checkpoint that regulates
the cellular activities of T lymphocytes. By causing T cell fatigue to encourage immune
evasion, the interaction between PD-L1 and PD-1 suppresses T cell activity.[51] The PDCD1 gene of the CD28 immunoglobulin superfamily encodes the type I transmembrane
protein PD-1, sometimes referred to as CD279. In 1992, Ishida et al. made the initial
discovery and report about it.[50] PD-1 is the marker of significant expression on natural killer T cells, activated
CD4+ T cells, CD8+ T cells, B cells, macrophages, dendritic cells (DCs), and monocytes.
Its production is initiated on activation of the TCR or BCR pathways. This expression
can be significantly enhanced by pro-inflammatory cytokines such as TNF. While this
increased expression of PD-1 on these immune cells contributes to the regulation of
the immune response, it has a relatively more identifiable role in immune suppression,
at least in tumors by facilitating tumor immune evasion.[52] PD-1 is a 288 amino acid protein that consists of a transmembrane domain, a cytoplasmic
domain, and a single extracellular Ig variable-type (IgV) domain.[53] The extracellular domain of PD-1 contains an Ig variable-type domain, which is necessary
for binding to its ligands, PD-L1 and PD-L2. This structure is similar to other members
of the CD28 superfamily of co-stimulatory receptors. The cytoplasmic domain of PD-1
contains N-terminal and C-terminal tyrosine residues, which are critical to the formation
of immunoreceptor tyrosine-based switch motifs (ITSMs) and immunoreceptor tyrosine-based
inhibitory motifs (ITIMs). Such motifs have been found to recruit downstream signaling
molecules that mediate inhibitory function in PD-1 through the suppression of T cell
activation and the consequent induced immune tolerance.[54]
[55] The latter is the primary signal transduction domain of PD-1 and is intimately associated
with effector T cell response activity. Two ligands are necessary for the biological
activities of PD-1: PD-L1 (also called B7-H1 or CD274) and PD-L2 (also called B7-H2
or CD273). In 1999, Dong et al. made the initial discovery of the former.[56] Activated pro-inflammatory cytokines are central regulators of further PD-L1 induction.
PD-L1 is widely expressed in T cells, B cells, DCs, cancer cells, macrophages, and
other immune cells. It is essentially PD-L1 that upregulation primarily facilitates
tumor immune evasion. Ligand binding to PD-1 on T cells suppresses its activation
and function, thereby preventing the tumor from being detected by immune surveillance
and thus facilitating the progression of the tumor. This immune evasion mechanism
is a critical contributor to resistance to immune-based therapies.[57]
PD-1/PD-L1 Axis in Immune Regulation and Cancer Immunotherapy
PD-1/PD-L1 Axis in Immune Regulation and Cancer Immunotherapy
Immune System Regulation
PD-1 (Programmed Death-1):
The immune checkpoint receptor PD-1 is expressed on the surface of B cells, myeloid
cells, and activated T cells. This is mostly done to maintain one's own tolerance
by averting autoimmune reactions and managing immune system activity. When PD-1 binds
to its ligands, it sends out an inhibitory signal that suppresses T cells, depriving
them of their natural immune system functions. When T cells become too activated during
an immunological response, the immune system stops trying to protect tissue.[55]
PD-L1 (Programmed Death-Ligand 1):
PD-L1 is a ligand expressed on the surface of numerous cells circulating in the body,
including antigen-presenting cells, some non-hematopoietic cells, and tumor cells.
The cytokine synthesis, cytotoxic activity, and T-cell proliferation are all inhibited
by this binding of PD-L1 to PD-1 of T cells. Consequently, this interaction serves
as an inhibitory checkpoint to moderate the severity of an immune response.[58]
Mechanism of Action in Immune Response:
Mechanism of Action in Immune Response:
When a T cell recognizes the antigen presented by an APC, it gets activated and goes
proliferative and thus gives rise to the immune response, but if the APC also expresses
PD-L1, then upon binding to PD-1 on the T cell, the activity of the T cell is suppressed;
this mechanism is indeed required for avoiding an autoimmune response and regulating
it. PD-L1 is inducibly expressed in response to inflammatory signals, and its expression
during the resolution of inflammation plays a role in dampening the immune response
once a pathogen is cleared.[59]
Role in Cancers:
Tumor Immune Evasion:
Most of the cancer cells escape the antitumor immune effect of T cells through the
PD-1/PD-L1 pathway. Tumor cells normally overexpress PD-L1, which then pairs with
PD-1 from T cells that infiltrate the tumor microenvironment. Its interaction suppresses
the activity of T cells, leading to immune escape by the tumor and favoring the unabashed
proliferation of cancer cells.[60]
Tumor Microenvironment:
As a rule, the tumor microenvironment is generally characterized as being essentially
immunosuppressive, with high expression of PD-L1 by stromal components and immune
cells within the tumor. Such a microenvironment may blunt the effectiveness of an
antitumor immune response.[61]
Adaptive Immune Resistance:
Tumors can adaptively upregulate PD-L1 expression under immune pressure, which includes
interferon-gamma (IFN-γ) secretions by activated T-cells. In this way, the cells are
allowed to resist immune attack by the tumors.[62]
Clinical Implication and Therapies:
Clinical Implication and Therapies:
Checkpoint Inhibition:
Anti-PD-1/PD-L1 Therapies: Monoclonal antibodies specific for PD-1, including nivolumab
and pembrolizumab, or for PD-L1, including atezolizumab and durvalumab, are used to
release the interaction between PD-1 and PD-L1, which activates T cells to function
properly and kill cancer. These inhibitors have produced excellent clinical outcomes
when used against many cancer types including, but not limited to, melanoma, non-small
cell lung cancer (NSCLC)/, and renal cell carcinoma, among others. However, not all
patients respond to these kinds of therapies, and the responses are likely to be dependent
on the tumor type and level of PD-L1 expression.[63]
Biomarkers:
Biomarker for predicting response to anti-PD-1/PD-L1 therapies: In use, PD-L1 expression
in tumors is common; however, this association is non-absolute and can be modifiable
with other factors like the tumor mutational burden and the expression of other immune
checkpoints.[64]
Combination Therapies:
Anti-PD-1/PD-L1 therapy often involves a combination with other therapeutic approaches,
including chemotherapy and/or radiation and/or targeted therapy and/or other immune
checkpoint inhibitors, to benefit the treatment outcomes. Combination therapies exploit
distinct mechanisms of action for optimal clinical benefits. For instance, chemotherapy
and radiation could enhance the presentation of tumor antigens and immunological activation
while targeted therapies may target specific mutations or pathways that are instrumental
for the survival of tumors. Hence, combining these therapies with immune checkpoint
inhibitors may help in blocking the different mechanisms of resistance, thus eliciting
a superior therapeutic response in cancer patients.[65]
Challenges and Side Effects:
Immune-Related Adverse Events (irAEs): Blocking of the PD-1/PD-L1 pathway can induce
autoimmune-like responses, leading to the reversion of inhibitory effects of the immune
system. Colitis, hepatitis, dermatitis, and endocrinopathies occur most commonly.[66]
Immune Checkpoint Regulation and Resistance
Immune Checkpoint Regulation and Resistance
All of them, namely activated CD4 and CD8 T cells, B cells, monocytes, natural killer
(NK) cells, and dendritic cells (DCs), express PD-1. Common γ chain cytokines, such
as IL-2, IL-7, IL-15, and IL-21, can stimulate T cells to produce PD-1. The Pdcd1
gene encodes PD-1. Another major transcription factor that activates the expression
of PD-1 is NFATc1, which is a crucial part of the signaling pathways that lead to
the activation of immune cells and regulate PD-1 in an immune response.[67]
[68] Other important transcriptional activators for PD-1 expression are the T-box transcription
factor TBX21, known as T-bet, forkhead box O 1 (Foxo1), and interferon regulatory factor 9 (IRF9), among others, and these regulate
the differentiation and function of immune cells. T-bet, for example, is involved
in T-helper cell differentiation as well as in the development of cellular immunity,
while Foxo1 and IRF9 are regulators that ensure the modulation of the immune response
as well as gene activation linked to T-cell activation. Taken together, these transcriptional
regulators account for PD-1 expression whose activity modulates T cell responses-including
all those processes that help support the maintenance of immune tolerance and which
control anti-tumor immunity.[69] The PD-1 ligands are type I transmembrane glycoproteins PD-L1 also known as B7-H1
or CD274, and PD-L2 also known as B7-DC or CD273. Although the sequence similarity
between PD-L1/PD-L2 with other members of the B7 family is around 20%, PD-L1 and PD-L2
share around 40% identity in their acidic regions. These ligands bind to PD-1 on immune
cells such that it inhibits T cell activation, an important function for modulating
the immune response, including the suppression of immune responses against tumors.[70] PD-Ls express themselves in various ways. Mast cells originating from bone marrow,
DCs, macrophages, mesenchymal stem cells, and T and B cells all constitutively express
PD-L1.[71] Activated DCs, macrophages, mast cells originating from bone marrow, and more than
50% of peritoneal B1 cells express PD-L2, in contrast to PD-L1.[72] On T cells, the γ chain cytokines IL-2, IL-7, and IL-15 can induce PD-L1 expression;
on CD19+ B cells, IL-21 stimulated PD-L1 expression. PD-Ls are also expressed on B
cells in response to LPS or BCR activation.[73] IFN-γ and IL-10 treatment has been shown to induce expression of both PD-L1 and
PD-L2 ligands in monocytes. In dendritic cells (DCs), PD-L2 expression has been shown
to be inducible, especially by IL-4 and granulocyte-macrophage colony-stimulating
factor (GM-CSF). It suppresses the immune response by interaction between PD-1 on
immune cells with its ligands, PD-L1 and PD-L2 on tumor cells. It is negative for
antitumor immunity and allows the evasion of immunosurveillance by tumor cells. Tumor
cells may use this resistance to immune-based therapies by defending themselves from
attacks through an engagement of immunity on PD-1.[74]
[75]
[76]
Immune Checkpoint Inhibitor Resistance
Immune Checkpoint Inhibitor Resistance
Regarded as one of the most promising approaches to cancer treatment is immunotherapy.
T cells' ability to suppress tumor cells and maintain their antitumor potential could
be maintained by blocking the PD-1/PD-L1 interaction.[77]
[78] Over fifteen cancer types have verified the superiority of the five PD-1/PD-L1 blocking
monoclonal antibodies that the U.S. FDA has approved thus far. However, immune checkpoint
inhibitors have a comparatively greater prevalence of initial resistance than chemotherapy
and molecular targeted therapy, which reduces their efficacious therapeutic advantages.
With a high percentage of partial responders, monotherapy's efficacy for PD-1/PD-L1
blocking was rarely greater than 40%.[79] Additionally, most patients experience acquired resistance following an initial
response to PD-1/PD-L1 inhibition, which ultimately results in the advancement of
the disease or recurrence.
Resistance mechanisms to PD-1 blocking therapy are complex, dynamic, and interdependent.
This resistance is attributed to several tumor cell-intrinsic and -extrinsic factors
such as expression of PD-L1, tumor neoantigen expression and presentation, associated
cellular signaling pathways, the tumor microenvironment (TME), relevant immune genes,
and epigenetic changes. This will interfere with the ability of immune cells to recognize,
become activated, and respond against tumor cells, thereby leading to mechanisms impede
the immune system loss of therapeutic efficacy.
The Mechanism of Resistance to PD-1/PD-L1 Blockade
The Mechanism of Resistance to PD-1/PD-L1 Blockade
|
Mechanism
|
Description
|
Reference
|
|
PD-L1 expression
|
There may be a correlation between increased local immune cytolytic activity and clinical
response and PD-L1/2 expression.
|
[80]
|
|
Lack of effective antigen presentation
|
The main reason some tumors are unresponsive to PD-1/PD-L1 blocker therapy is that
T-cells cannot recognize the tumor. T-cells can fail to recognize cancerous cells
via a variety of mechanisms, such as tumor antigens absent from the tumor, loss of
expression of HLA (human leukocyte antigen), and even dysfunctional mutations in B2M
(beta-2-microglobulin). All these mechanisms impede the immune system to identify
and attack tumor cells; in this way, they lead to immune evasion and resistance to
the attack mechanism.
|
[81]
|
|
Cellular singnaling pathways
|
|
|
|
PI3K/AKT pathway
|
Reduced production of IFN-γ, granzyme B, and reduced CD8 T-cell infiltration was all
strongly linked with loss of PTEN-mediated PI3K/AKT activation.
|
[82]
|
|
WNT/β-catenin pathway
|
T-cell exclusion from malignancies may be caused by constitutive WNT signaling pathway
and b-catenin stabilization.
|
[83]
|
|
JAK/STAT/IFN-γ pathway
|
By downregulating or altering molecules such as IFNGR1/2, JAK2, and IRF1, cancer cells
may be able to evade the effects of IFN-γ.
|
[84]
|
|
MAPK pathway
|
MAPK signaling inhibits T-cell recruitment and function through the induction of VEGF
and IL-8.
|
[85]
|
|
Tumor microenvironment
|
|
|
|
Immunosuppressive cells
|
|
|
|
Exhaustion T-cells
|
PD-1high fatigue and dysfunctional T-cells PD-1 inhibition is ineffective against
T-cells.
|
[86]
|
|
Tregs
|
IL-10, IL-35, and TGF-β secretion are used to suppress effector T-cell (Teff) responses.
|
[87]
|
|
MDSCs
|
encourage tumor invasion, angiogenesis, and metastasis.
|
[88]
|
|
TAMs
|
A worse prognosis is linked to higher TAM frequencies.
|
[89]
|
|
Immunosuppressive cytokines
|
Frequently secreted by tumors or macrophages to inhibit anti-tumor immune responses
locally, this group of molecules includes TGF-β, CCL5, CCL7, CXCL8, IDO, etc.
|
[90]
|
|
Inhibitory receptors
|
In addition to PD-1, overexpression of several other inhibitory receptors, such as
TIM3, CTLA4, LAG3, and BTLA, is linked to T-cell function suppression and resistance
to PD-1/PD-L1 blocking therapy.
|
[91]
|
|
Immune related genes
|
|
|
|
IPRES signatures
|
Another association with primary resistance to PD-1/PD-L1 blockade and the TME was
detected through co-enrichment of a set of 26 transcriptome signatures known as **IPRES
signatures**. IPRES signatures consist of specific mechanisms of immune resistance
in the TME, responsible for the failure of treatments aiming at blocking PD-1/PD-L1.
|
[92]
|
|
Epigenetic modification
|
|
|
|
DNA methylation and histone acetylation
|
Although several epigenetic modifications may result in the change of expression of
genes that are involved in the immune response, they could influence antigen processing
and presentation, immune evasion, and T-cell exhaustion. Histone deacetylase inhibitors
and DNA methyltransferase inhibitors may reverse the process of immune suppression
through several mechanisms.
|
[93]
|
Checkpoint Inhibitor Combination Therapies in Combination with Chemotherapy
Checkpoint Inhibitor Combination Therapies in Combination with Chemotherapy
Mechanism: Chemotherapy often results in the immunogenic death of numerous cells,
which releases tumor-associated antigens for the immune system to recognize, which
may lead to an increase in the immuno-reactivity of the tumors. The immune response
against tumor cells is subsequently strengthened by chemotherapy when combined with
PD-1/PD-L1 inhibitors.[94]
Clinical Evidence: The use of chemotherapy in combination with pembrolizumab-an anti-PD-1
monoclonal antibody-resulted in an overall survival improved by 51% and a progression-free
survival improved by 58% more than with chemotherapy alone in NSCLC.[95]
In Combination with Targeted Therapies Mechanism:
In Combination with Targeted Therapies Mechanism:
Targeted therapies, such as tyrosine kinase inhibitors, selectively target signaling
pathways in cancer cells. These treatments alter the composition of the tumor microenvironment
to be more susceptible to immune attack. Combinations with PD-1/PD-L1 inhibitors synergistically
potentiate anti-tumor responses.[96]
Clinical Evidence: In renal cell carcinoma, the combination of axitinib, a VEGFR TKI,
and pembrolizumab, has thus shown significant improvements in patient outcomes compared
to standard treatments.[97]
Combination with Other Immune Checkpoint Inhibitors
Combination with Other Immune Checkpoint Inhibitors
Mechanism: Besides the PD-1/PD-L1 pathway, other immune checkpoints such as CTLA-4
(Cytotoxic T-Lymphocyte Antigen 4) are important in the suppression of an immune response.
CTLA-4 mechanism acts to inhibit T-cell activation thereby avoiding hyper-immune response
to normal tissues. Combination of PD-1/PD-L1 inhibitors with CTLA-4 inhibitors may
significantly enhance the activation of the immune system through the simultaneous
blockade of two other distinct inhibitory pathways. This dual inhibition may boost
T-cell function, which could result in better and more potent and long-lasting immune
responses against tumors and thereby potentially afford a therapeutic advantage with
immunotherapy in fighting cancer.[98]
Clinical Evidence: An important combination in the treatment of melanoma was using
an agent that inhibited PD-1, combined with an antagonist of CTLA-4, namely ipilimumab.
Thus, a combination therapy showed far greater OS compared with the survival associated
with monotherapy alone using nivolumab or ipilimumab. The blockage of both the pathways,
PD-1, and CTLA-4, is synergistically enhanced and successfully leads to a robustly
heightened immune response, thus effectively targeting and eradicating the melanoma.
This combination therapy has been approved for melanoma. Many in the community take
this in stride but mark a milestone in immuno-oncology.[99]
Combination with Radiation Therapy
Combination with Radiation Therapy
Mechanism: Radiation therapy can cause direct tumor cell death and modulate the immune
microenvironment by increasing the release of tumor antigens. Combining radiation
with PD1/PDL1 blockade can amplify the anti-tumor immune response. Clinical Evidence:
In selected malignancies, such as HNSCC, the addition of radiation to PD-1 inhibitors
has shown clinical benefit.[100]
Combination with Oncolytic Viruses
Combination with Oncolytic Viruses
Mechanism: Oncolytic viruses selectively infect and kill cancer cells, releasing tumor
antigens and thus activating the immune system. The combination of oncolytic viruses
with inhibitors of PD-1/PD-L1 further augments the anti-tumor immune response.[101]
Clinical Evidence: Early clinical trials combining an oncolytic virus, talimogene
laherparepvec (T-VEC), with PD-1 inhibitors have shown promising results in patients
with melanoma.[102]
Combination with CAR-T Cell Therapy
Combination with CAR-T Cell Therapy
Mechanism: Adoptive transfer of CAR-T cells targeting tumor antigens. However, T-cells
in the tumor environment become exhausting. PD-1/PD-L1 inhibitors rejuvenate these
T-cells to act more effectively against the tumor cells. Clinical Evidence: Studies
are still ongoing, but it is suggested that, from preclinical models, a combination
of CAR-T therapy with PD-1 blockade improves outcomes in hematologic malignancies.[103]
Combination with Cancer Vaccines
Combination with Cancer Vaccines
Mechanism: Cancer vaccines stimulate the immune system against recognition and attack
of tumor cells. Combinations with inhibitors of PD-1/PD-L1 can further amplify this
response.[104]
Clinical Evidence: Combinations of personalized cancer vaccines with inhibitors of
PD-1 in melanoma and other malignancies have yielded encouraging evidence of increased
immune activity and clinical benefit.[105]
Combination Therapy with PD-1/PD-L1 Inhibitors: Clinical Trial Insights and Approvals[10]
Combination Therapy with PD-1/PD-L1 Inhibitors: Clinical Trial Insights and Approvals[10]
|
Target
|
Check point
inhibitors
|
Combined intervention
|
Combined category
|
condition
|
Phase
|
Trail number
|
|
PD-1
|
Nivolumab
|
Tivozanib
|
Anti-angiogenesis therapy
|
RCC
|
Phase 1,2
|
NCT03136627
|
|
|
cabozantinib
|
Anti-angiogenesis therapy
|
Brest cancer
|
Phase 2
|
NCT03316586
|
|
|
Ramucirumab
|
Anti-angiogenesis therapy
|
Gastric cancer
|
Phase 1,2
|
NCT02999295
|
|
|
Carotuximab
|
Anti-angiogenesis therapy
|
NSCLC
|
Phase 1
|
NCT03181308
|
|
|
Pemetrexed + paclitaxel + veliparib + carboplatin
|
chemotherapy
|
NSCLC
|
Phase1
|
NCT02944396
|
|
|
Carboplatin + pemetrexed + ipilimumab
|
Chemotherapy + CTLA-4 antibody
|
NSCLC
|
Phase2
|
NCT03256136
|
|
|
lpilimumab
|
CTLA-4 antibody
|
melanoma
|
Phase 1
|
NCT01621490
|
|
|
Lpilimumab + SBRT
|
CTLA-4 antibody + radiotherapy
|
RCC; Kidney cancer
|
Phase 2
|
NCT03065179
|
|
|
Ipilimumab radiotherapy
|
CTLA-4 antibody + radiotherapy
|
melanoma
|
Phase 1
|
NCT02659540
|
|
|
Ipilimumab surgery
|
CTLA-4 antibody + surgery
|
Head and neck carcinoma
|
Phase 1,2
|
NCT03003637
|
|
|
Pilimumab + enzalutamide
|
CTLA-4 antibody + targeted therapy (AR)
|
Prostate cancer
|
Phase 2
|
NCT02601014
|
|
Pembrolizumab
|
Bevacizumab
|
Anti-angiogenesis therapy
|
RCC
|
Phase 1,2
|
NCT02348008
|
|
|
Anlotinib
|
Anti-angiogenesis therapy
|
NSCLC
|
Phase 1,2
|
NCT04670107
|
|
|
Lenalidomide
|
Anti-angiogenesis therapy
|
Blood Cancer
|
Phase 1
|
NCT01953692/KEYNOTE-013
|
|
|
Bevacizumab + cyclophosphamide
|
Anti-angiogenesis therapy + chemotherapy
|
Ovarian cancer; fallopian tube cancer; peritoneal cancer
|
Phase 2
|
NCT02853318
|
|
|
Necitumumab
|
Targeted therapy (EGFR)
|
NSCLC
|
Phase 1
|
NCT02451930
|
|
|
PEGPH20
|
Targeted therapy (HA)
|
Solid tumor
|
Phase 1
|
NCT02563548
|
|
PD-1
|
Cemiplimab
|
Hypofractionated radiotherapy + cyclophosphamide + docetaxel + carboplatin + GM- CSF + paclitaxel+
pemetrexed
|
Radiotherapy + chemotherapy
|
Malignancy
|
Phase 1
|
NCT02383212
|
|
PD-L1
|
Atezolizumab
|
Anlotinib
|
Anti-angiogenesis therapy
|
NSCLC
|
Phase 1,2
|
NCT04670107
|
|
|
Bevacizumab +carboplatin +paclitaxel
|
Anti-angiogenesis therapy+ chemotherapy
|
NSCLC
|
Phase 3
|
NCT0236614
|
|
|
Bevacizumab + cobimetinib
|
Anti-angiogenesis therapy +targeted therapy (MEK1)
|
Gastrointestinal tumor
|
Phase 1
|
NCT02876224
|
|
Durvalumab
|
Bevacizumab
|
Anti-angiogenesis therapy
|
HER-2 negative breast cancer Early
|
Phase 1
|
NCT02802098
|
|
|
Paclitaxel
|
Chemotherapy
|
TNBC
|
Phase 1, 2
|
NCT02628132
|
|
|
Tremelimumab
|
CTLA-4 antibody
|
Head and Neck cancer
|
Phase 3
|
NCT02369874
|
|
|
Tremelimumab + SBRT
|
CTLA-4 antibody + radiotherapy
|
Pancreatic cancer
|
Phase 1, 2
|
NCT02311361
|
|
|
Dabrafenib + trametinib
|
Targeted therapy (BRAF) + targeted therapy (MEK1/2)
|
Melanoma
|
Phase 1
|
NCT02027961
|
|
Avelumab
|
Axitinib
|
Anti-angiogenesis therapy
|
GBM
|
Phase 2
|
NCT0329131
|
|
|
Axitinib
|
Anti-angiogenesis therapy
|
RCC
|
Phase 1
|
NCT02493751
|
|
|
Talazoparib + chemotherapy
|
Chemotherapy + targeted therapy (PARP)
|
Ovarian cancer
|
Phase 3
|
NCT03642132
|
|
|
Cisplatin + 5-FU + mitomycin + radiation therapy
|
Radiotherapy + chemotherapy
|
Bladder cancer
|
Phase 2
|
NCT03617913
|
Challenges of Combining CAR-T and PD-1/PD-L1 Therapies
Challenges of Combining CAR-T and PD-1/PD-L1 Therapies
The challenges of combining CAR-T and PD-1/PD-L1 therapies, as outlined in the article,
include the following
T-cell Exhaustion
CAR-T cells are naturally exhausted. Due to constant exposure to tumor antigens, they
perform less effectively with time. A significantly confusing aspect of this is that
the PD-1/PD-L1 pathway actively interferes with the activation of CAR-T cells as well
as the carrying out of their functions as effector cells.
It is more crucial in the setting of solid tumors or diseases with a high tumor burden,
leading to poor function and persistence of CAR-T cells and thereby lessening the
long-term efficacy.[106]
Immunosuppressive Tumor Microenvironment (TME):
Immunosuppressive Tumor Microenvironment (TME):
-
The tumor microenvironment usually consists of immunosuppressive elements that also
limit the activity of CAR-T cells and immune checkpoint inhibitors. In tumors with
high levels of PD-L1, such as certain cancers, the TME prevents the CAR-T cells from
reaching their full potential therapeutic effects.
-
The therapeutic environment then becomes immunosuppressive in nature, reducing CAR-T
cell cytotoxicity and the secretion of cytokines, further impairing the effectiveness
of combination therapy.[107]
Dose Optimization and Toxicity:
Dose Optimization and Toxicity:
Challenges in dose optimization for CAR-T cells with administration of PD-1/PD-L1
inhibitors: CAR-T cells variably expand in vivo, and thus it becomes unpredictable
how they might interact with PD-1 inhibitors, thereby producing inconsistent responses
and unpredictable toxicity.
-
- In the clinic, severe CRS and other toxicities, including neurotoxicity, are at
risk. Although controllable, the occurrence and severity of CRS cannot be predicted
when both therapies are used in concert.[108]
Limited Persistence:
In the case of CAR-T cells, persistence is very short with patients, and cancer relapse
will occur. While PD-1 inhibition brings back T-cells and fosters performance, how
long does the reinvigorated T-cell stay in existence long enough to control or eradicate
the tumor.[109]
Clinically Uncertain Outcomes:
Clinically Uncertain Outcomes:
While preclinical studies hold great promise with findings of excitingly good results,
the clinical response to CAR-T and PD-1/PD-L1 combination therapy has been entirely
inconsistent. Some patients experience remission for a long period, whereas others
relapse or show no response at all to the treatment. Such inconsistency makes it difficult
to make proper strategies for an effective therapy.[110]
Conclusion
Through genetic engineering, T cells can eradicate cancers in CAR-T cell therapy,
a novel type of cellular treatment. Treating B-cell hematologic malignancies with
KYMRIAH and YESCARTA, which target CD19, has proven effective. For targeted solid
tumors, more than 200 clinical trials involving targeted antigens and CAR-T treatment
have been started. Antigens Targeted for Solid Tumors: Mesothelin (MSLN), ganglioside
(GD2), glypican-3 (GPC3), HER2, CEA, EGFR/EGFRvIII, PSMA, PSCA, and claudin 18.2 are
a few examples of targeted antigens.
Immune System "Brake" Mechanism: Cancer cells activate the immune system's "checkpoints,"
like PD-1/PD-L1 and CTLA-4, to evade immune cell killing. Inhibiting these checkpoints
has proven a highly effective anticancer therapy and has been applied in cancers,
including melanoma, lung, liver, and breast cancer, with antibodies. Immune Checkpoints
and Cancer Escape: Immune checkpoints promote tolerance to self and prevent autoimmunity
and tissue injury. These pathways are hijacked by the cancer cells as one mechanism
of immune evasion. PD-1/PD-L1 Pathway: The PD-1/PD-L1 pathway inhibits T-cell activation,
an important immune system mechanism. Blockade of PD-1/PD-L1 is documented to have
a limited clinical response of ∼40%.
A promising area of progress in the treatment of cancer would be a combination of
CAR-T cell therapy with PD-1/PD-L1 checkpoint inhibitors, particularly for solid tumors,
which have been very difficult to hit by CAR-T alone. Indeed, it has the possibility
of overcoming two of the major challenges: T-cell exhaustion and the tumor microenvironment
as an immunosuppressive environment. Reinvigoration of exhausted T cells and thus
improving their persistence and function, the blockade of PD-1/PD-L1 will dramatically
increase the impact of CAR-Ts in attacking the tumor. However, several challenges
exist. Toxicity, particularly CRS, and neurotoxicity, especially with combination
approaches, should be closely monitored. Dose optimization is another challenge because
the CAR-T cell expansion is extremely unpredictable leading to variable response outcomes.
Lastly, although the preclinical studies have been promising, the clinical responses
have been highly variable among individuals making it challenging to create an across-the-board
treatment strategy.
Future research would then be focused on fine-tuning these therapies to minimize risk
while maximizing efficacy. This will involve the better development of predictive
biomarkers and understanding the more specific mechanisms by which resistance may
arise and how best to integrate these treatments with other modalities including chemotherapy,
radiation, and targeted therapies. The approach clearly bodes well for radical improvements
in the treatment of solid tumors and post-long-term outcomes in cancer immunotherapy.
Abbreviations
CAR:
Chimeric Antigen Receptor
TME:
Tumor Microenvironment
PD-1:
Programmed Cell Death Protein 1
PD-L1:
Programmed Death-Ligand 1
CTLA-4:
Cytotoxic T-Lymphocyte-Associated Protein 4
CD:
Cluster of Differentiation
FDA:
Food and Drug Administration
TCR:
T Cell Receptor
APC:
Antigen-Presenting Cells
MSLN :
Mesothelin
GD2:
Ganglioside D2
GPC3:
Glypican-3
HER2:
Human Epidermal Growth Factor Receptor 2
CEA:
Carcinoembryonic Antigen
EGFR:
Epidermal Growth Factor Receptor
PSMA:
Prostate-Specific Membrane Antigen
PSCA:
Prostate Stem Cell Antigen
CRS:
Cytokine Release Syndrome
IL:
Interleukin
IDO:
Indoleamine 2,3-dioxygenase
TIM-3:
T Cell Immunoglobulin and Mucin Domain-Containing Protein 3
LAG-3:
Lymphocyte Activation Gene-3
NFATc1:
Nuclear Factor of Activated T-Cells Cytoplasmic 1
Foxo1:
Forkhead Box O1
IFN-γ:
Interferon Gamma
TGF-β:
Transforming Growth Factor Beta
VEGF:
Vascular Endothelial Growth Factor
SCLC:
Small Cell Lung Cancer
NSCLC:
Non-Small Cell Lung Cancer
TNBC:
Triple-Negative Breast Cancer
NK:
Natural Killer
HLA:
Human Leukocyte Antigen
JAK:
Janus Kinase
STAT:
Signal Transducer and Activator of Transcription
WNT:
Wingless/Integrated
MAPK:
Mitogen-Activated Protein Kinase
MDSC:
Myeloid-Derived Suppressor Cells
TAMs:
Tumor-Associated Macrophages
CAR-T:
Chimeric Antigen Receptor T-Cell Therapy
AR:
Androgen Receptor
SBRT:
Stereotactic Body Radiation Therapy
DC:
Dendritic Cells
HA:
Hyaluronic Acid
MEK:
Mitogen-Activated Protein Kinase Kinase
GM-CSF:
Granulocyte-Macrophage Colony-Stimulating Factor
B2M:
Beta-2 Microglobulin
TILs:
Tumor-Infiltrating Lymphocytes
DAMPs:
Damage-Associated Molecular Patterns
CRT:
Calreticulin
ATP:
Adenosine Triphosphate
HMGB1:
High-Mobility Group Box 1
TLR4:
Toll-Like Receptor 4
P2RX7:
Purinergic Receptor P2 × 7
CD91:
Cluster of Differentiation 91
MDSCs:
Myeloid-Derived Suppressor Cells
CRISPR:
Clustered Regularly Interspaced Short Palindromic Repeats
mAbs:
Monoclonal Antibodies
ICIs:
Immune Checkpoint Inhibitors
RCC:
Renal Cell Carcinoma
CT:
Chemotherapy
IRF9:
Interferon Regulatory Factor 9
ITIM:
Immunoreceptor Tyrosine-Based Inhibition Motif
ITSM:
Immunoreceptor Tyrosine-Based Switch Motif
IFNGR:
Interferon Gamma Receptor
IRF1:
Interferon Regulatory Factor 1
BCR:
B-Cell Receptor
CD8:
Cluster of Differentiation 8
B7-H1:
Another name for PD-L1
B7-H2:
Another name for PD-L2
DCs:
Dendritic Cells
MYC:
Myelocytomatosis Oncogene
CD274:
Another name for PD-L1
CD279:
Another name for PD-1
TBX21:
T-box Transcription Factor 21 (also known as T-bet)
PI3K:
Phosphatidylinositol 3-Kinase
Akt:
Protein Kinase B
EGFRvIII:
Variant III of Epidermal Growth Factor Receptor
PS:
Performance Status
ICB:
Immune Checkpoint Blockade
BTLA:
B- and T-Lymphocyte Attenuator
CXCL8:
C-X-C Motif Chemokine Ligand 8
CCL5:
C-C Motif Chemokine Ligand 5
CCL7:
C-C Motif Chemokine Ligand 7
CD4:
Cluster of Differentiation 4
AR:
Androgen Receptor (may have been duplicated but context is important)
TAM:
Tumor-Associated Macrophages
CRP:
C-Reactive Protein
VEGFR:
Vascular Endothelial Growth Factor Receptor
TME:
Tumor Microenvironment (already mentioned but emphasized in context)
MHC:
Major Histocompatibility Complex
PDCD1:
Programmed Cell Death Protein 1 (gene name for PD-1)
B7-DC:
Another name for PD-L2
IFN-I:
Type I Interferon
GLOBOCAN:
Global Cancer Observatory (cancer statistics project)
TLR:
Toll-Like Receptor
LPS:
Lipopolysaccharide
IRF1:
Interferon Regulatory Factor 1
NF-κB:
Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells
SBRT:
Stereotactic Body Radiation Therapy (repeated but included for emphasis)
OS:
Overall Survival
PFS:
Progression-Free Survival
NMPA:
National Medical Products Administration (China)
SCLC:
Small Cell Lung Cancer (mentioned earlier, but useful for context)
P2RX7:
Purinergic Receptor P2 × 7 (related to immune response)
LAG3:
Lymphocyte-Activation Gene 3 (also mentioned earlier)
Bibliographical Record
Rishi Kant, Prashanjit Roy, Amandeep Kaur, Ranjeet Kumar. Enhancing CAR-T Efficacy:
The Role of Anti PD-1/PD-L1 Checkpoint Inhibitors in Modern Cancer Treatment. Journal
of Coloproctology 2025; 45: s00451809675.
DOI: 10.1055/s-0045-1809675
